Crystallographic and 19F NMR fragment-libraries

Title: A Winning Combination: Crystallographic and 19F NMR Fragment-Libraries in Drug Discovery

In the pursuit of new drug candidates, crystallographic and 19F NMR fragment-libraries have emerged as powerful tools in the field of drug discovery. Crystallography allows for the determination of protein-ligand structures, while 19F NMR provides insights into ligand-target interactions. Combining these two techniques offers a comprehensive platform for fragment-based drug discovery (FBDD). This blog will explore the significance and potential of crystallographic and 19F NMR fragment-libraries in revolutionizing the process of drug discovery.

Key Points:

  1. Crystallographic Fragment-Libraries: Crystallographic techniques, such as X-ray crystallography and cryo-electron microscopy, enable researchers to visualize the three-dimensional structure of protein-ligand complexes. Crystallographic fragment-libraries typically consist of small, diverse fragments that are soaked in protein crystals and their binding interactions are determined by solving the crystal structure. This technique provides detailed information about the binding mode and protein-ligand interactions, guiding the optimization process.
  2. Insights into Binding Interactions: Crystallography reveals the exact location and orientation of fragments within the binding site. This information elucidates critical binding interactions, such as hydrogen bonding, hydrophobic interactions, and electrostatic interactions. By studying these interactions, medicinal chemists can further optimize fragments for improved binding affinity and selectivity, leading to the development of highly potent lead compounds.
  3. 19F NMR Fragment-Libraries: 19F NMR is a powerful technique for studying ligand-target interactions in solution. In 19F NMR fragment-libraries, fluorine-19 is incorporated into the fragments, providing a unique signal that can be detected and analyzed. By monitoring changes in the 19F NMR spectrum upon binding, researchers can gain insights into fragment binding interactions and dynamics, enabling the selection and optimization of fragments with optimal binding properties.
  4. Advantages of 19F NMR: 19F NMR offers several advantages in fragment-based drug discovery. Firstly, it allows for the screening of fragment libraries in solution, mimicking the physiological environment. Secondly, as fluorine is a biologically inert element, it minimally perturbs the fragment’s chemical structure and binding mode. Thirdly, the 19F NMR signal is highly specific, allowing for the quantification and characterization of ligand-target interactions, including binding kinetics and affinities.
  5. Combining Crystallography and 19F NMR: The synergy between crystallographic and 19F NMR techniques is apparent in fragment-based drug discovery. Crystallography provides a static view of binding interactions, while 19F NMR captures dynamic information. By combining these two techniques, researchers can validate crystallographic hits identified from fragment libraries and obtain complementary insights into binding modes and dynamic behavior. This comprehensive approach guides the optimization of fragments into high-affinity lead compounds.
  6. Rational Design and Library Expansion: Crystallography and 19F NMR enable rational design strategies for fragment libraries. Protein-ligand structures obtained from crystallography can guide the selection and design of fragments that interact with specific protein residues. 19F NMR can validate and optimize these fragments based on their binding affinity and dynamics. Moreover, both techniques can guide the expansion of fragment libraries to cover a broader chemical space, enhancing the chances of discovering novel and diverse lead compounds.

Combining crystallographic and 19F NMR fragment-libraries offers a potent platform for accelerating drug discovery. Crystallography provides structural insights into protein-ligand interactions, while 19F NMR enables the characterization of ligand-target binding events in solution. This synergistic approach guides the selection, optimization, and expansion of fragment libraries, leading to the development of potent and selective lead compounds. As crystallographic and 19F NMR techniques continue to advance, their integration will play an increasingly vital role in modern drug discovery, unlocking new therapeutic possibilities for a wide range of diseases.